This proposal addresses a critical aspect of the HIV-1 epidemic by seeking to better understand the roles of viral proteins and polydrug abuse on the development of HIV neurocognitive disorders (HAND). HIV quickly enters the brain and infects macrophages and microglia rather than neurons. While HAART can effectively control this replication, HAND prevalence is not reduced in parallel, indicating that virus replication is not responsible for all neuropathology. Viral proteins that may come from infected astroctyes even during viral suppression are thought to cause neuronal damage both directly and indirectly. Individual drugs of abuse, such as cocaine or morphine, synergize with viral toxins through effects on astrocytes to exacerbate inflammation and oxidative stress. However, polydrug use predominates among substance abusers in the US and no studies to date have examined the combinations of drugs with HIV neurotoxins. The first aim of this proposal is targeted to better understand the potential synergy between polydrug abuse (speedball) and HIV neurotoxins. A second aim is to develop a rat model of speedball to study the motor and memory effects of polydrug abuse with these virotoxins. These goals will be approached using application of speedball and Tat or Vpr to in vitro primary cultures of astrocytes and neurons to study exacerbated oxidative stress and inflammation as a possible mechanism for synergistic neurotoxicity. In addition, rats treated with cocaine, morphine or speedball will be assessed for motor and memory function followed by post mortem histological analyses of prooxidant environment and neuronal damage and death. This research will lead to a better understanding of the overlapping roles of viral toxins and multiple drug abuse in generating oxidative stress and inflammation that appear to be a key to understanding the development and progression of HAND. In addition, the work will generate an essential new tool to study, in a biological setting, the extent and nature of the motor and memory defects that occur in HIV neurocognitive disorders, including the mechanistic role of oxidants. This model is expected to be instrumental in the design of translational studies for discovery of new treatment strategies to prevent HAND development and progression in a drug abuse setting. PUBLIC HEALTH RELEVANCE: HIV-1 infection and drug abuse are two medically and socially important issues in the US. These epidemics exist independently, but also have significant overlap including a possible synergistic contribution to neurocognitive disorders. This proposal seeks to better define and understand the combined effects of drug abuse and HIV infection in neuropathology, as well as to generate baseline data on to permit targeted in vivo studies of the contributions of HIV and drugs to NeuroAIDS. Such information can be used to improve long term management and reduce the morbidity associated with these illnesses.